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*
Department of Pathology, University of Verona, Verona, Italy;
Department of Neurological Sciences, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore Policlinico, and "Dino Ferrari" Center, Milan, Italy;
Department of Pediatrics, Pathology, and Microbiology-Immunology, Dalhousie University, Halifax, Nova Scotia, Canada;
Institute of Cell Biology, Center for Molecular Biology of Inflammation, University of Muenster, and Max-Planck-Institut, Muenster, Germany; and
¶ Department of Pathology, Stanford University, Stanford, CA 94305
Lymphocyte recruitment into the brain is a critical event in the
pathogenesis of multiple sclerosis and experimental autoimmune
encephalomyelitis. We developed a novel intravital microscopy model to
directly analyze through the skull the interactions between lymphocytes
and the endothelium in cerebral venules of mice. No adhesive
interactions were observed between lymphocytes and the nonactivated
endothelium in the cerebral microcirculation. When brain venules were
activated by pretreating mice with TNF-
or LPS, proteolipid protein
139–151 autoreactive T lymphocytes rolled and arrested; notably, only
a few peripheral lymph node cells rolled and firmly adhered. Abs
anti-P-selectin glycoprotein ligand-1 and anti-E- and
P-selectin blocked tethering and rolling of autoreactive lymphocytes,
suggesting that P-selectin glycoprotein ligand-1/endothelial selectins
are critical in the recruitment of lymphocytes in inflamed brain
venules. E- and P-selectin were expressed on cerebral vessels upon in
vivo activation and had a patchy distribution during the preclinical
phase of active and passive experimental autoimmune encephalomyelitis.
LFA-1/ICAM-1 and 4 integrins/VCAM-1 supported rolling,
but were not relevant to rolling velocity. Firm arrest was mainly
mediated by LFA-1 and ICAM-1. Pretreatment of autoreactive lymphocytes
with pertussis toxin blocked integrin-dependent arrest, implicating a
requirement for Gi protein-dependent signaling in vessels
from nonlymphoid districts. In conclusion, our data unveils the
molecular mechanisms controlling the recruitment of autoreactive
lymphocytes in inflamed cerebral vessels and suggest new insights into
the pathogenesis of autoimmune inflammatory diseases of the
CNS.
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